RNAi Used to Regulate Tumor Growth in Mouse Model

Their research was reported in the February 3, 2003, online edition of Nature Genetics.

Post-transcriptional gene silencing (PTGS), which was initially considered a bizarre phenomenon limited to petunias and a few other plant species, is now one of the most competitive topics in molecular biology. In the last few years, it has become clear that PTGS occurs in both plants and animals and has roles in viral defense and transposon silencing mechanisms. Perhaps most thought-provoking, however, is the emerging use of PTGS and RNA interference (RNAi)-- PTGS initiated by the introduction of double-stranded RNA (dsRNA)--as a tool to knock out expression of specific genes in a variety of organisms.

In the current study, investigators from Cold Spring Harbor Laboratory (NY, USA) studied the effect of RNAi on the p53 tumor suppressor gene. Mice with no active p53 develop lymphomas much sooner and in a more aggressive, highly invasive form than when the p53 gene is present.

The researchers reconstituted the blood cells of mice by first irradiating the animals to destroy their endogenous, bone marrow supply of hematopoietic stem cells, and then injected the mice with a fresh supply of hematopoietic stem cells that had been engineered through RNAi to produce low, medium, or high levels of p53.

Results showed that short hairpin RNAs (shRNAs) produced distinct phenotypes ranging from benign lymphoid hyperplasias to highly disseminated lymphomas. In all cases, the severity and type of disease correlated with the extent to which specific shRNAs inhibited p53 activity.

The authors concluded that, "RNAi can stably suppress gene expression in stem cells and reconstituted organs derived from those cells. Therefore, RNAi is a convenient alternative to traditional, laborious, and less flexible homologous recombination-based gene knockout strategies for studying the effects of reduced gene expression in a wide variety of settings.”




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